4-phenyl-5-thioxo-4,5-dihydro-1,3,4-thiadiazole-2-sulfonamide



United States Patent O 4-PI-[ENYL-5-THIOX0-4,5-DIHYDRO-1,3,4-

THIAPTAZOLE-Z-SULFONAMIDE No Drawing. Application April '30, 1958 ..-Serial N0.731,886 I 1 Claim. (Cl. 260-306.7)

This invention relates to a new compound, 4-phenyl-5- thioxo-4,5-dihydro-1,3,4-thiadiazole-Z-sulfonamide, having the following structural formula:

In the preparation of the novel compound of the invention, 4-phenyl-5-thioxo-4,S-dihydro-1,3,4-thiadazole-2- thiol is first converted to the corresponding sulfenamide by oxidative condensation with an amide-forming nitrogen compound which can be carried out in one step [see Carr, Smith, and Alliger, J. Org. Chem. 14: 921-34 (1949); Tschunkur and Kohler, U.S. Patent 2,045,888; Ashworth, U.S. Patent 2,268,467; Carr, U.S. Patent 2,271,834; and Harman, U.S. Patents 2,191,656-7], or in two steps via an N-chloroamine [see Hanslick, US. Patent 2,261,024; British Patent 377,730; and Alliger, U.S. Patents 2,495,085 and 2,581,921], or in two steps via the disulfide [see Busch, Ber. 29: 2127 (1896); Tschunkur and Kohler, U.S. Patent 2,045,888]. The obtained sulfenamide is then treated with a strong oxidizing agent to convert it to the desired sulfonamide. The oxidizing agent, advantageously aqueous potassium permanganate, is added gradually with stirring and with cooling, if desired, advantageously to a solution of the sulfenamide in an inert solvent such as acetone, pyridine, dioxane, and like polar solvents such as commonly are used as media for permanganate oxidations. Other strong oxidizing agents of an alkaline character, that is, which are either eifective in an alkaline solution or produce in the oxidation an alkaline component, can be used. Alkaline hydrogen peroxide and sodium peroxide, for example, could be used in place of potassium permanganate. Acidic oxidations using hydrogen peroxide in acetic acid, chromic acid, nitric acid, permanganic acid, and the like, can be used. The oxidizing agent advantageously can be dissolved in a solvent (water, for example, is suitable for potassium permanganate) and the solution slowly added to the sulfenamide solution. If the rate of addition is properly adjusted, excessive heating will be avoided. Ordinarily it will be sufiicient if the rate of addition of the oxidizing agent is so correlated with the capacity of the apparatus to dissipate heat as to keep the temperature below the decomposition temperature for either the sulfenamide used or the sulfonamide produced in the reaction mixture, whichever is the lower. As this temperature will vary according to the decomposition temperature of the compounds involved, no hard and fast rule can be given, but, in general, it will be suificient if the temperature is kept below about sixty degrees centigrade. Any lower reactive tem perature can be used. At lower temperatures, however, the rate of reaction is reduced so that it is ordinarily desirable not to operate at temperatures below about minus five degrees centigrade. Ordinarily a temperature between about zero and about fifty degrees centigrade is suitable. When the reaction is complete, the desired sulfonamide, after acidification to free it from its salt, if such is formed, can then be recovered in any suitable manner, as by filtration, centrifugation, solvent extraction, or the like, and can, if desired, be purified by recrystallization from a solvent.

When ammonia is used the unsubstituted amide is obtained. By substituting methylamine for ammonia, the corresponding N-methyl sulfonamide is obtained. In the like manner, by substituting secondary amines and other primary amines in the above reactions, there are also obtained the corresponding N,N-dimethyl, N-n butyl, N-isobutyl, 'N-sec-butyl, N-tert-butyl, N,N-diisopropyl, N-methylN-ethyl, N-Z-aminoethyl, N-(Z-ethylhexyl), N-cyclohexyl, N-methyl-N-cyclohexyl, N-Z-methylcyclohexyl, N-cyclopentyl, and like N-monoand N-dilower-alkyl and cycloalkyl sulfonamides; N-2-pyridyl, N-Z-thiazolyl, N-Z-pyrimidyl, and like N-heterocyclic sulfonamides; and N-phenyl, N-methyl-N-phenyl, N-2- thienyl, N-thenyl, N-Z-furyl, N-furfuryl, N-tolyl, N- benzyl, N-phenethyl, and like N-aryl and N-aralkyl sulfonamides. Also by substituting the ammonia by a heterocyclic secondary amine such as piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, and the like, as well as the lower-alkyl derivatives thereof, such as 2-methylpiperidine, 2,2-dimethylpyrrolidine, and the like, there are obtained the corresponding sulfonamides in which the amide nitrogen is comprised in a heterocycle. Thus the NH group in the above formulas can be replaced by the group -NR'R" in which R and R", respectively, are hydrogen, lower-alkyl, lower-cycloalkyl, lower-aryl', or lower-aralkyl, and together a 'lower-alkylene, lower-oxalkylene, or lowerazalkylene radical forming with the nitrogen a five to six membered heterocyclic ring.

The invention may be more fully understood by reference to the following examples which are illustrative only and not intended to be limiting.

EXAMPLE 1 A. 4 phenyl 5 thioxo 4,5 dihydro 1,3,4- thiadiazole-Z-sulfenamide To a solution of five grams of sodium hydroxide in 200 milliliters of water was added 26.6 grams (0.1 mole) of 4-phenyl-5-thioxo-4,5-dihydro-1,3,4-thiadiazole-2-thiol [Busch, Ber. 27: 2512 (1894)]. This solution and milliliters of ten percent sodium hypochlorite solution were added simultaneously to 300 milliliters of concentrated ammonium hydroxide which was cooled to zero degrees centigrade, and vigorously stirred. The resulting 4 phenyl 5 thioxo 4,5 dihydro 1,3,4 thiadiazole- 2-sulfenamide was recovered by filtration and thoroughly washed with ice water. Because of the tendency to decompose, this sulfenamide Was used without further purification.

This sulfenamide can also be prepared by the method of Busch, Ber. 29: 2127 (1896), by treating the corresponding disulfide with alcoholic ammonia.

The sulfenamide thus produced is useful as an accelerator in the vulcanization of rubber or as an intermediate for the preparation of the corresponding sulfonamide in accordance with the following:

B. 4 phenyl 5 thioxo 4,5 dihydro 1,3,4 thiadz'azole-Z-sulfonamide A solution of 300 milligrams of the sulfenamide of Example 1A dissolved in acetone was treated with a five percent aqueous potassium permanganate solution until the latter was no longer decolorized. The reaction mixture was filtered, the solid (manganese dioxide) was washed with warm water, and the combined filtrates were concentrated to remove acetone. Acidification of the solution with concentrated hydrochloric acid gave the desired 4 phenyl 5 thioxo 4,5 dihydro 1,3,4 thiadiazole-Z-sulionamide, which was then recrystallized two times from ethylene dichloride Skellysolve B. It melted at 191.5-194 degrees centigrade and weighed fifty milligrams.

Analysis.Ca1cu1ated: N, 15.37; S, 35.19. Found: N, 15.13; S, 34.57.

The sulfonamide thus produced is useful as an antibacterial agent and has anti-tubercular properties.

This application is a continuation-in-part of copending applications Serial No. 462,113, filed October 13, 1954, and Serial No. 723,136, filed March 24, 1958.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claim.

I claim:

4-phenyl 5 thioxo 4,5 dihydro 1,3,4 thiadiazole- 2-sulfonamide.

OTHER REFERENCES Kulberg et al.: Chem. Abstracts, vol. 48. col. 5016 (1954). 

